{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T23:53:17Z","timestamp":1792713197877,"version":"4.5.0"},"reference-count":85,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,1,7]],"date-time":"2021-01-07T00:00:00Z","timestamp":1609977600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,1,7]],"date-time":"2021-01-07T00:00:00Z","timestamp":1609977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Semin Immunopathol"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The conventional perception asserts that immunology is the science of \u2018discrimination\u2019 between self and non-self. This concept is however no longer tenable as effector cells of the adaptive immune system are first conditioned to be tolerant to the body\u2019s own antigens, collectively known as self until now. Only then attain these effectors the responsiveness to non-self. The acquisition of this essential state of tolerance to self occurs for T cells in the thymus, the last major organ of our body that revealed its intricate function in health and disease. The \u2018thymus\u2019 as an anatomical notion was first notably documented in Ancient Greece although our present understanding of the organ\u2019s functions was only deciphered commencing in the 1960s. In the late 1980s, the thymus was identified as the site where clones of cells reactive to self, termed \u2018forbidden\u2019 thymocytes, are physically depleted as the result of a process now known as negative selection. The recognition of this mechanism further contributed to the belief that the central rationale of immunology as a science lies in the distinction between self and non-self. This review will discuss the evidence that the thymus serves as a unique lymphoid organ able to instruct T cells to recognize and be tolerant to harmless self before adopting the capacity to defend the body against potentially injurious non-self-antigens presented in the context of different challenges from infections to exposure to malignant cells. The emerging insight into the thymus\u2019 cardinal functions now also provides an opportunity to exploit this knowledge to develop novel strategies that specifically prevent or even treat organ-specific autoimmune diseases.<\/jats:p>","DOI":"10.1007\/s00281-020-00831-y","type":"journal-article","created":{"date-parts":[[2021,1,7]],"date-time":"2021-01-07T22:17:28Z","timestamp":1610057848000},"page":"5-14","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["The thymus and the science of self"],"prefix":"10.1007","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8733-7284","authenticated-orcid":false,"given":"Vincent","family":"Geenen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,7]]},"reference":[{"key":"831_CR1","first-page":"1","volume-title":"Thymus Transcriptome and Cell Biology","author":"V Geenen","year":"2019","unstructured":"Geenen V, Savino W (2019) History of the thymus \u2013 from a vestigial organ to the programming of immune self-tolerance. In: Passos GA (ed) Thymus Transcriptome and Cell Biology. Springer, London, pp 1\u201318"},{"key":"831_CR2","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1210\/endo-5-5-543","volume":"5","author":"J Hammar","year":"1921","unstructured":"Hammar J (1921) The new views at the morphology of the thymus gland and their hearing on the problem of the function of the thymus. Endocrinology 5:543\u2013573","journal-title":"Endocrinology"},{"key":"831_CR3","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1210\/jcem-6-2-117","volume":"6","author":"H Selye","year":"1946","unstructured":"Selye H (1946) The general adaptation syndrome and the diseases of adaptation. J Clin Endocrinol Metab 6:117\u2013130","journal-title":"J Clin Endocrinol Metab"},{"key":"831_CR4","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1016\/S0140-6736(61)90693-6","volume":"2","author":"JF Miller","year":"1961","unstructured":"Miller JF (1961) The immune function of the thymus. Lancet 2:748\u2013749","journal-title":"Lancet"},{"key":"831_CR5","first-page":"70","volume-title":"The immunologically competent cell: its nature and origin","author":"PB Medawar","year":"1963","unstructured":"Medawar PB (1963) discussion after Miller JFAP and Osoba D. role of the thymus in the origin of immune competence. In: Westenholme GEW, Knight J (eds) The immunologically competent cell: its nature and origin. Ciba Foundation Study Group, London, p 70"},{"key":"831_CR6","first-page":"424","volume":"66","author":"P Ehrlich","year":"1900","unstructured":"Ehrlich P (1900) The Croonian lecture: on immunity. Proc Soc Lond Biol 66:424","journal-title":"Proc Soc Lond Biol"},{"key":"831_CR7","doi-asserted-by":"crossref","first-page":"4027","DOI":"10.1073\/pnas.71.10.4027","volume":"71","author":"S Tonegawa","year":"1974","unstructured":"Tonegawa S, Steinberg C, Dube S, Bernardini A (1974) Evidence for somatic generation of antibody diversity. Proc Natl Acad Sci USA 71:4027\u20134031","journal-title":"Proc Natl Acad Sci USA"},{"key":"831_CR8","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1016\/0092-8674(84)90444-6","volume":"73","author":"M Malissen","year":"1984","unstructured":"Malissen M, Minard K, Mjolsness et al (1984) Mouse T cell antigen receptor: structure and organization of constant and joining segments encoding the beta polypeptide. Cell 73:1101\u20131110","journal-title":"Cell"},{"key":"831_CR9","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1126\/science.3616623","volume":"237","author":"H Ohki","year":"1987","unstructured":"Ohki H, Martin C, Corbel C, Coltey M, le Douarin N (1987) Tolerance induced by thymic epithelial grafts in birds. Science 237:1032\u20131035","journal-title":"Science"},{"key":"831_CR10","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/0092-8674(87)90568-X","volume":"49","author":"JW Kappler","year":"1987","unstructured":"Kappler JW, Roehm N, Marrack P (1987) T cell tolerance by clonal elimination in the thymus. Cell 49:273\u2013280","journal-title":"Cell"},{"key":"831_CR11","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/332040a0","volume":"332","author":"HR MacDonald","year":"1988","unstructured":"MacDonald HR, Glasebrook AL, Schneider R et al (1988) T-cell receptor V\u03b2 use predicts reactivity and tolerance to Mlsa-encoded antigens. Nature 332:40\u201345","journal-title":"Nature"},{"key":"831_CR12","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1038\/333742a0","volume":"333","author":"P Kisielow","year":"1988","unstructured":"Kisielow P, Bl\u00fcthman H, Staerz UD et al (1988) Tolerance in T-cell receptor transgenic mice involves deletion of non-mature CD4 + 8+ thymocytes. Nature 333:742\u2013746","journal-title":"Nature"},{"key":"831_CR13","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1002\/eji.1830100310","volume":"10","author":"RG Scollay","year":"1980","unstructured":"Scollay RG, Butcher EC, Weissman IL (1980) Thymus cell migration. Quantitative aspects of cellular traffic from the thymus to the periphery in mice. Eur J Immunol 10:210\u2013218","journal-title":"Eur J Immunol"},{"key":"831_CR14","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.4049\/jimmunol.155.3.1151","volume":"155","author":"S Sakaguchi","year":"1995","unstructured":"Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chain (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151\u20131164","journal-title":"J Immunol"},{"key":"831_CR15","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1146\/annurev.immunol.25.022106.141623","volume":"30","author":"SZ Josefowicz","year":"2012","unstructured":"Josefowicz SZ, Liu LF, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Ann Rev Immunol 30:531\u2013564","journal-title":"Ann Rev Immunol"},{"key":"831_CR16","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.immuni.2019.01.020","volume":"50","author":"JB Wong","year":"2019","unstructured":"Wong JB, Tanaka A, Sakaguchi S (2019) Human FOXP3+ regulatory T cell heterogeneity and function in autoimmunity and cancer. Immunity 50:302\u2013316","journal-title":"Immunity"},{"key":"831_CR17","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/j.1600-065X.1993.tb00645.x","volume":"135","author":"P Matzinger","year":"1993","unstructured":"Matzinger P (1993) Why positive selection? Immunol Rev 135:81\u2013117","journal-title":"Immunol Rev"},{"key":"831_CR18","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/nyas.14089","volume":"1455","author":"V Geenen","year":"2019","unstructured":"Geenen V, Trussart C, Michaux H, Halouani A, Ja\u00efdane H, Coll\u00e9e C, Renard C, Daukandt M, Ledent P, Martens H (2019) The presentation of neuroendocrine self-peptides in the thymus: an essential event for individual life and vertebrate survival. Ann NY Acad Sci 1455:113\u2013126","journal-title":"Ann NY Acad Sci"},{"key":"831_CR19","volume-title":"Neural Modulation of Immunity","year":"1985","unstructured":"Guillemin R, Cohn M, Melnechuk T (eds) (1985) Neural Modulation of Immunity. Raven Press, New York"},{"key":"831_CR20","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1084\/jem.11.2.326","volume":"11","author":"I Ott","year":"1909","unstructured":"Ott I, Scott JC (1909) The action of glandular extracts upon the contractions of the uterus. J Exp Med 11:326\u2013330","journal-title":"J Exp Med"},{"key":"831_CR21","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/S0021-9258(18)49238-1","volume":"205","author":"V du Vigneaud","year":"1953","unstructured":"du Vigneaud V, Ressler C, Trippett S (1953) The sequence of amino acids in oxytocin, with a proposal for the structure of oxytocin. J Biol Chem 205:949\u2013953","journal-title":"J Biol Chem"},{"key":"831_CR22","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1152\/physrev.2001.81.2.629","volume":"81","author":"G Gimpl","year":"2001","unstructured":"Gimpl G, Fahrenholz F (2001) The oxytcin receptor system: structure, function, and regulation. Physiol Rev 81:629\u2013683","journal-title":"Physiol Rev"},{"key":"831_CR23","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1124\/pr.120.019398","volume":"72","author":"C Sue Carter","year":"2020","unstructured":"Sue Carter C, Kenkel WM, MacLean EL, Wilson SR, Perkeybille AM et al (2020) Is oxytocin nature\u2019s medicine. Pharmacol Rev 72:829\u2013861","journal-title":"Pharmacol Rev"},{"key":"831_CR24","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1126\/science.3961493","volume":"232","author":"V Geenen","year":"1986","unstructured":"Geenen V, Legros JJ, Franchimont P, Baudrihaye M, Defresne M, Boniver J (1986) The thymus as a neuroendocrine organ: Coexistence of oxytocin and neurophysin in the human thymus. Science 232:508\u2013511","journal-title":"Science"},{"key":"831_CR25","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1111\/j.1749-6632.1987.tb35746.x","volume":"496","author":"V Geenen","year":"1987","unstructured":"Geenen V, Legros JJ, Franchimont P et al (1987) The thymus as a neuroendocrine organ. Synthesis of vasopressin and oxytocin in human thymic epithelium. Ann NY Acd Sci 496:56\u201366","journal-title":"Ann NY Acd Sci"},{"key":"831_CR26","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1159\/000124938","volume":"47","author":"V Geenen","year":"1988","unstructured":"Geenen V, Defresne MP, Robert F, Legros JJ, Franchimont P, Boniver J (1988) The neurohormonal thymic microenvironment: immunocytochemical evidence that thymic nurse cells are neuroendocrine cells. Neuroendocrinology 47:365\u2013368","journal-title":"Neuroendocrinology"},{"key":"831_CR27","doi-asserted-by":"crossref","first-page":"20572","DOI":"10.1073\/pnas.1213069109","volume":"109","author":"Y Nakagawa","year":"2012","unstructured":"Nakagawa Y, Ohigashi I, Nitta T, Sakata M, Tanaka K, Murata S, Kanagawa O, Takahama Y (2012) Thymic nurse cells provide microenvironment for secondary T cell receptor a rearrangement in cortical thymocytes. Proc Natl Acad Sci U S A 109:20572\u201320577","journal-title":"Proc Natl Acad Sci U S A"},{"key":"831_CR28","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.jneuroim.2004.08.007","volume":"158","author":"I Hansenne","year":"2005","unstructured":"Hansenne I, Rasier G, P\u00e9queux C, Brilot F, Renard C, Breton C, Greimers R, Legros JJ, Geenen V, Martens HJ (2005) Ontogenesis and functional aspects of oxytocin and vasopressin gene expression in the thymus network. J Neuroimmunol 158:67\u201375","journal-title":"J Neuroimmunol"},{"key":"831_CR29","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1159\/000054324","volume":"67","author":"H Martens","year":"1998","unstructured":"Martens H, Kecha O, Charlet-Renard C, Defresne MP, Geenen V (1998) Neurohypophysial peptides activate phosphorylation of focal adhesion kinases in immature thymocytes. Neuroendocrinology 67:282\u2013289","journal-title":"Neuroendocrinology"},{"key":"831_CR30","first-page":"229","volume":"340","author":"P Reichardt","year":"2010","unstructured":"Reichardt P, Dornbach B, Gunzer M (2010) APC, T cells and the immune synapse. Curr Top Microbiol Immunol 340:229\u2013249","journal-title":"Curr Top Microbiol Immunol"},{"key":"831_CR31","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/0167-5699(96)10023-2","volume":"17","author":"H Martens","year":"1996","unstructured":"Martens H, Goxe GV (1996) The thymic repertoire of neuroendocrine self-peptides in T-cell life and death. Immunol Today 17:312\u2013317","journal-title":"Immunol Today"},{"key":"831_CR32","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1046\/j.1365-2826.1998.00269.x","volume":"10","author":"V Geenen","year":"1998","unstructured":"Geenen V, Kecha O, Martens H (1998) Thymic expression of neuroendocrine self-peptide precursors: role in T-cell survival and self-tolerance. J Neuroendocrinol 10:811\u2013822","journal-title":"J Neuroendocrinol"},{"key":"831_CR33","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/0167-5699(93)90195-Q","volume":"14","author":"V Geenen","year":"1993","unstructured":"Geenen V, Kroemer G (1993) Multiple ways to cellular immune tolerance. Immunol Today 14:573\u2013575","journal-title":"Immunol Today"},{"key":"831_CR34","doi-asserted-by":"publisher","unstructured":"Perniola R (2018) Twenty years of AIRE. Front Immunol 9:98 https:\/\/doi.org\/10.3389\/fimmu.2018.00098\/full","DOI":"10.3389\/fimmu.2018.00098\/full"},{"key":"831_CR35","first-page":"55","volume":"22","author":"V Geenen","year":"1993","unstructured":"Geenen V, Vandersmissen E, Cormann-Goffin N, Martens H, Legros JJ, Degiovanni G, Benhida A, Martial J, Franchimont P (1993) Membrane translocation and relationship with MHC class I of a human thymic neurophysin-like molecule. Thymus 22:55\u201366","journal-title":"Thymus"},{"key":"831_CR36","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S0167-0115(96)00105-X","volume":"67","author":"H Martens","year":"1996","unstructured":"Martens H, Malgrange B, Robert F, Charlet C, de Groote D, Heymann D, Godard A, Soulillou JP, Moonen G, Geenen V (1996) Cytokine production by human thymic epithelial cells: Control by the immune recognition of the neurohypophysial self-antigen. Regul Pept 67:39\u201345","journal-title":"Regul Pept"},{"key":"831_CR37","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1146\/annurev.iy.11.040193.001241","volume":"11","author":"HG Rammensee","year":"1993","unstructured":"Rammensee HG, Falk K, R\u00f6tschke O (1993) Peptides naturally presented by MHC class I molecules. Ann Rev Immunol 11:213\u2013244","journal-title":"Ann Rev Immunol"},{"key":"831_CR38","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/S0165-5728(97)00052-0","volume":"76","author":"Y Vanneste","year":"1997","unstructured":"Vanneste Y, Ntodou-Thom\u00e9 A, Vandersmissen E et al (1997) Identification of neurotensin-related peptides in human thymic epithelial cell membranes and relationship with major histocompatibility complex class I molecules. J Neuroimmunol 76:161\u2013166","journal-title":"J Neuroimmunol"},{"key":"831_CR39","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1038\/308196a0","volume":"308","author":"BA Kyewski","year":"1984","unstructured":"Kyewski BA, Fathman CG, Kaplan HS (1984) Intrathymic presentation of circulating non-major histocompatibility complex antigens. Nature 308:196\u2013199","journal-title":"Nature"},{"key":"831_CR40","doi-asserted-by":"crossref","first-page":"e187","DOI":"10.3389\/fnins.2013.00187","volume":"7","author":"V Geenen","year":"2013","unstructured":"Geenen V, Bodart G, Henry S et al (2013) Programming of neuroendocrine self in the thymus and its defect in the development of neuroendocrine autoimmunity. Front Neurosc 7:e187","journal-title":"Front Neurosc"},{"key":"831_CR41","doi-asserted-by":"crossref","first-page":"6707","DOI":"10.1073\/pnas.91.14.6707","volume":"5","author":"C Jolic\u0153ur","year":"1994","unstructured":"Jolic\u0153ur C, Hanahan D, Smith KM (1994) T-cell tolerance toward a transgenic beta-cell antigen and transcription of endogenous pancreatic genes in the thymus. Proc Natl Acad Sci U S A 5:6707\u20136711","journal-title":"Proc Natl Acad Sci U S A"},{"key":"831_CR42","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1093\/intimm\/9.9.1355","volume":"9","author":"KM Smith","year":"1997","unstructured":"Smith KM, Olson DC, Hirose R, Hanahan D (1997) Pancreatic gene expression in rare cells of thymic medulla: evidence for functional contribution to T-cell tolerance. Int Immunol 9:1355\u20131365","journal-title":"Int Immunol"},{"key":"831_CR43","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1007\/s001090000146","volume":"78","author":"L Klein","year":"2000","unstructured":"Klein L, Kyewski B (2000) \u201cPromiscuous\u201d expression of tissue antigens in the thymus: a key to T-cell tolerance and autoimmunity. J Mol Med 78:483\u2013494","journal-title":"J Mol Med"},{"key":"831_CR44","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1038\/ni723","volume":"2","author":"J Derbinsky","year":"2001","unstructured":"Derbinsky J, Schulte A, Kyewski B, Klein L (2001) Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2:1032\u20131039","journal-title":"Nat Immunol"},{"key":"831_CR45","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1084\/jem.20031677","volume":"199","author":"J Gotter","year":"2004","unstructured":"Gotter J, Brors B, Hergenhahn M, Kyewski B (2004) Medullary epithelial cells of the thymus express a highly diverse selection of tissue-specific genes co-localized in chromosomal clusters. J Exp Med 199:155\u2013165","journal-title":"J Exp Med"},{"key":"831_CR46","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1084\/jem.20082449","volume":"206","author":"C Koble","year":"2009","unstructured":"Koble C, Kyewski B (2009) The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J Exp Med 206:1505\u20131513","journal-title":"J Exp Med"},{"key":"831_CR47","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/S1074-7613(04)00111-6","volume":"20","author":"D Mathis","year":"2014","unstructured":"Mathis D, Benoist C (2014) Back to central tolerance. Immunity 20:509\u2013516","journal-title":"Immunity"},{"key":"831_CR48","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1146\/annurev.immunol.23.021704.115601","volume":"24","author":"B Kyewski","year":"2016","unstructured":"Kyewski B, Klein L (2016) A central role for central tolerance. Ann Rev Immunol 24:571\u2013606","journal-title":"Ann Rev Immunol"},{"key":"831_CR49","doi-asserted-by":"crossref","first-page":"4651","DOI":"10.4049\/jimmunol.176.8.4651","volume":"176","author":"I Hansenne","year":"2006","unstructured":"Hansenne I, Charlet-Renard C, Greimers R, Geenen V (2006) Dendritic cell differentiation and immune tolerance to insulin-related peptides in Igf2-deficient mice. J Immunol 176:4651\u20134657","journal-title":"J Immunol"},{"key":"831_CR50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/icb.1972.1","volume":"50","author":"FM Burnet","year":"1973","unstructured":"Burnet FM (1973) A reassessment of the forbidden clone hypothesis of autoimmune diseases. Aust J Exp Biol Med 50:1\u20139","journal-title":"Aust J Exp Biol Med"},{"key":"831_CR51","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.diabres.2012.05.023","volume":"98","author":"V Geenen","year":"2012","unstructured":"Geenen V (2012) Thymus and type 1 diabetes: an update. Diabetes Res Clin Pract 98:26\u201332","journal-title":"Diabetes Res Clin Pract"},{"key":"831_CR52","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1002\/dmrr.182","volume":"17","author":"O Kecha-Kamoun","year":"2001","unstructured":"Kecha-Kamoun O, Achour I, Martens H, Collette J, Lefebvre PJ, Greiner DL, Geenen V (2001) Thymic expression of insulin-related genes in an animal model of type 1 diabetes. Diab Metab Res Rev 17:146\u2013152","journal-title":"Diab Metab Res Rev"},{"key":"831_CR53","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/ng0397-289","volume":"15","author":"P Vafiadis","year":"1997","unstructured":"Vafiadis P, Bennett ST, Todd JA, Nadeau J, Grabs R, Goodyer CG, Wickramasinghe S, Colle E, Polychronakos C (1997) Insulin expression in human thymus is modulated by INS VTNR alleles at the IDDM2 locus. Nat Genet 15:289\u2013292","journal-title":"Nat Genet"},{"key":"831_CR54","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/ng0397-293","volume":"15","author":"A Pugliese","year":"1997","unstructured":"Pugliese A, Zeller M, Fernandez A Jr et al (1997) The insulin gene is transcribed in human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet 15:293\u2013297","journal-title":"Nat Genet"},{"key":"831_CR55","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.2337\/diabetes.51.5.1383","volume":"51","author":"AA Chentoufi","year":"2002","unstructured":"Chentoufi AA, Polychronakos C (2002) Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance. Diabetes 51:1383\u20131390","journal-title":"Diabetes"},{"key":"831_CR56","doi-asserted-by":"crossref","first-page":"2579","DOI":"10.2337\/db10-0476","volume":"59","author":"S Noso","year":"2010","unstructured":"Noso S, Kataoka K, Kawabata Y, Babaya N, Hiromine Y, Yamaji K, Fujisawa T, Aramata S, Kudo T, Takahashi S, Ikegami H (2010) Insulin transactivator Mafa regulates intrathymic expression of insulin and affects susceptibility to type 1 diabetes. Diabetes 59:2579\u20132587","journal-title":"Diabetes"},{"key":"831_CR57","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1007\/BF00195143","volume":"73","author":"R Paschke","year":"1995","unstructured":"Paschke R, Geenen V (1995) Messenger RNA expression for a TSH receptor variant in the thymus of a 2-yr old child. J Mol Med 73:577\u2013580","journal-title":"J Mol Med"},{"key":"831_CR58","doi-asserted-by":"crossref","first-page":"5918","DOI":"10.4049\/jimmunol.161.11.5918","volume":"161","author":"M Sospedra","year":"1998","unstructured":"Sospedra M, Ferrer-Francesch X, Dominguez O et al (1998) Transcription of a broad range of self-antigens in human thymus suggesting a role for central mechanisms in tolerance towards peripheral antigens. J Immunol 161:5918\u20135929","journal-title":"J Immunol"},{"key":"831_CR59","doi-asserted-by":"crossref","first-page":"2228","DOI":"10.1172\/JCI119032","volume":"98","author":"M Murakami","year":"1996","unstructured":"Murakami M, Hosoi Y, Negishi T, Kamiya Y, Miyashita K, Yamada M, Iriuchijima T, Yokoo H, Yoshida I, Tsushima Y, Mori M (1996) Thymic hyperplasia in patients with Graves\u2019 disease. Identification of thyrotropin receptor in human thymus. J Clin Invest 98:2228\u20132234","journal-title":"J Clin Invest"},{"key":"831_CR60","doi-asserted-by":"crossref","first-page":"3415","DOI":"10.1093\/hmg\/ddr247","volume":"20","author":"R Colobran","year":"2011","unstructured":"Colobran R, del Pilar AM, Faner R et al (2011) Association of an SNP with intrathymic expression and Graves\u2019 disease: a role for defective tolerance. Hum Mol Genet 20:3415\u20133423","journal-title":"Hum Mol Genet"},{"key":"831_CR61","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1172\/JCI44583","volume":"121","author":"H Lv","year":"2011","unstructured":"Lv H, Havari E, Pinto S, Gottumukkala RVSRK, Cornivelli L, Raddassi K, Matsui T, Rosenzweig A, Bronson RT, Smith R, Fletcher AL, Turley SJ, Wucherpfennig K, Kyewski B, Lipes MA (2011) Impaired thymic tolerance to a-myosin directs autoimmunity to the heart in mice and humans. J Clin Invest 121:1561\u20131573","journal-title":"J Clin Invest"},{"key":"831_CR62","first-page":"723","volume":"14","author":"AE Handel","year":"2018","unstructured":"Handel AE, Sarosh R, Holl\u00e4nder GA (2018) The role of thymic tolerance in CNS autoimmune disease. Nat Rev Neurosci 14:723\u2013734","journal-title":"Nat Rev Neurosci"},{"key":"831_CR63","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1126\/science.1075958","volume":"298","author":"MS Anderson","year":"2002","unstructured":"Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D (2002) Projection of an immune self-shadow within the thymus by the Aire protein. Science 298:1395\u20131401","journal-title":"Science"},{"key":"831_CR64","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/ng1297-399","volume":"17","author":"The Finnish-German APECED Consortium","year":"1997","unstructured":"The Finnish-German APECED Consortium (1997) An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PhD-type zinc-finger domains. Nat Genet 17:399\u2013403","journal-title":"Nat Genet"},{"key":"831_CR65","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/ng1297-393","volume":"17","author":"K Nagamine","year":"1997","unstructured":"Nagamine K, Peterson P, Scott H et al (1997) Positional cloning of the APECED gene. Nat Genet 17:393\u2013398","journal-title":"Nat Genet"},{"key":"831_CR66","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.immuni.2008.08.007","volume":"29","author":"M Irla","year":"2008","unstructured":"Irla M, Hugues S, Gill J, Nitta T, Hirosaka Y et al (2008) Autoantigen-specific interactions with CD4+ thymocytes control medullary thymic epithelial cell cellularity. Immunity 29:451\u2013463","journal-title":"Immunity"},{"key":"831_CR67","doi-asserted-by":"crossref","unstructured":"Akiyama T, Shino Y, Yanai H, Qin J, Oshima D et al The tumor necrosis factor family receptor RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29:423\u2013437","DOI":"10.1016\/j.immuni.2008.06.015"},{"key":"831_CR68","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.immuni.2013.08.005","volume":"39","author":"JM Gardner","year":"2013","unstructured":"Gardner JM, Metzger TC, Mc Mahon EJ, Au-Yeung BB, Krawisz AK et al (2013) Extrathymic Aire-expressing cells are a distinct bone marrow-derived population that induces functional inactivation of CD4+ T cells. Immunity 39:560\u2013572","journal-title":"Immunity"},{"key":"831_CR69","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.3389\/fimmu.2018.02120","volume":"9","author":"AE Handel","year":"2018","unstructured":"Handel AE, Shakama-Dorn N, Zhanybekova S, Maio S, Graedel AN et al (2018) Comprehensively profiling the chromatin architecture of tissue-restricted antigen expression in thymic epithelial cells over development. Front Immunol 9:2120","journal-title":"Front Immunol"},{"key":"831_CR70","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1101\/gr.171645.113","volume":"24","author":"SN Sansom","year":"2014","unstructured":"Sansom SN, Shikana-Dorn N, Zhanybekova S, Nusspaumer G, Macaulay K et al (2014) Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia. Genome Res 24:1918\u20131931","journal-title":"Genome Res"},{"key":"831_CR71","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1016\/j.cell.2015.10.013","volume":"163","author":"H Takaba","year":"2015","unstructured":"Takaba H, Morishita Y, Tomfuji Y et al (2015) Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell 163:975\u2013987","journal-title":"Cell"},{"key":"831_CR72","doi-asserted-by":"publisher","first-page":"892","DOI":"10.1038\/s41590-020-0717-2","volume":"21","author":"Y Tomofuji","year":"2020","unstructured":"Tomofuji Y, Takaba H, Suzuki H et al (2020) Chd4 choreographs self-antigen expression for central immune tolerance. Nat Immunol 21:892\u2013901. https:\/\/doi.org\/10.1038\/s41590-020-0717-2","journal-title":"Nat Immunol"},{"key":"831_CR73","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1749-8104-9-6","volume":"9","author":"MJ Eckler","year":"2014","unstructured":"Eckler MJ, Larkan KA, McKennan WL, Katzman S, Guo C et al (2014) Multiple conserved regulatory domains promte Fezf2 expression in the developing cerebral cortex. Neural Dev 9:6","journal-title":"Neural Dev"},{"key":"831_CR74","doi-asserted-by":"crossref","first-page":"e56221","DOI":"10.7554\/eLife.56221","volume":"9","author":"J Baran-Gale","year":"2020","unstructured":"Baran-Gale J, Morgan MD, Maio S, Dhalla F, Calvo-Asensio I, Deadman ME, Handel AE, Maynard A, Chen S, Green F, Sit RV, Neff NF, Darmanis S, Tan W, May AP, Marioni JC, Ponting CP, Holl\u00e4nder GA (2020) Ageing compromises mouse thymus function and remodels epithelial cell differentiation. eLife 9:e56221","journal-title":"eLife"},{"key":"831_CR75","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.2337\/db10-1360","volume":"60","author":"S Fourlanos","year":"2011","unstructured":"Fourlanos S, Perry C, Gellert SA, Martinuzzi F, Mallone R et al (2011) Evidence that nasal insulin induces immune tolerance to insulin in adults with autoimmune diabetes. Diabetes 60:1237\u20131245","journal-title":"Diabetes"},{"key":"831_CR76","first-page":"191ra82","volume":"5","author":"BO Roep","year":"2013","unstructured":"Roep BO, Solvason N, Gottlieb PA, Abreu JRF, Harrison LC et al (2013) Plasmid-encoding proinsulin preserves C-peptide while specifically reducing proinsulin-specific CD8+ T cells. Sci Transl Med 5:191ra82","journal-title":"Sci Transl Med"},{"key":"831_CR77","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.coph.2010.04.005","volume":"10","author":"V Geenen","year":"2010","unstructured":"Geenen V, Mottet M, Dardenne O, Kermani H, Martens H, Francois JM, Galleni M, Hober D, Rahmouni S, Moutschen M (2010) Thymic self-antigens for the design of a negative\/tolerogenic self-vaccination against type 1 diabetes. Curr Opin Pharmacol 10:461\u2013472","journal-title":"Curr Opin Pharmacol"},{"key":"831_CR78","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1002\/(SICI)1099-0895(199803)14:1<95::AID-DMR200>3.0.CO;2-W","volume":"14","author":"V Geenen","year":"1998","unstructured":"Geenen V, Lef\u00e8bvre PJ (1998) The intrathymic expression of insulin-related genes: implications for pathophysiology and prevention of type 1 diabetes. Diab Metab Rev 14:95\u2013103","journal-title":"Diab Metab Rev"},{"key":"831_CR79","doi-asserted-by":"crossref","first-page":"11151","DOI":"10.1128\/JVI.00726-12","volume":"86","author":"H Ja\u00efdane","year":"2012","unstructured":"Ja\u00efdane H, Caloone D, Lobert PE et al (2012) Persistent infection of thymic epithelial cells with coxsackievirus B4 results in decreased expression of type 2 insulin-like growth factor. J Virol 86:11151\u201311162","journal-title":"J Virol"},{"key":"831_CR80","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1196\/annals.1337.008","volume":"1037","author":"V Geenen","year":"2004","unstructured":"Geenen V, Louis C, Martens H, The Belgian Diabetes Registry (2004) An insulin-like growth factor 2-derived self-antigen inducing a regulatory cytokine profile after presentation to peripheral blood mononuclear cells from DQ8+ type 1 diabetic adolescents: preliminary design of a thymus-based tolerogenic self-vaccination. Ann NY Acad Sci 1037:59\u201364","journal-title":"Ann NY Acad Sci"},{"key":"831_CR81","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1016\/j.jaci.2014.02.019","volume":"133","author":"G Yang","year":"2014","unstructured":"Yang G, Geng XR, Song JP, Wu Y, Yan H, Zhan Z, Yang L, He W, Liu ZQ, Qiu S, Liu Z, Yang PC (2014) Insulin-like growth factor 2 enhances regulatory T-cell functions and suppresses food allergy in an experimental model. J Allergy Clin Immunol 133:1702\u20131708","journal-title":"J Allergy Clin Immunol"},{"key":"831_CR82","doi-asserted-by":"crossref","first-page":"17941","DOI":"10.1074\/jbc.M113.515262","volume":"289","author":"XR Geng","year":"2014","unstructured":"Geng XR, Yang G, Li M, Song JP, Liu ZQ, Qiu S, Liu Z, Yang PC (2014) Insulin-like growth factor 2 enhances functions of antigen-specific regulatory B cells. J Biol Chem 289:17941\u201317950","journal-title":"J Biol Chem"},{"key":"831_CR83","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1146\/annurev-immunol-020711-075038","volume":"30","author":"T Boehm","year":"2012","unstructured":"Boehm T, Mccurley N, Sutoh Y et al (2012) VLR-based adaptive immunity. Ann Rev Immunol 30:203\u2013220","journal-title":"Ann Rev Immunol"},{"key":"831_CR84","doi-asserted-by":"crossref","first-page":"R1060","DOI":"10.1016\/j.cub.2014.09.070","volume":"24","author":"MF Flajnik","year":"2014","unstructured":"Flajnik MF (2014) Re-evaluation of the immune Big Bang. Curr Biol 24:R1060\u2013R1065","journal-title":"Curr Biol"},{"key":"831_CR85","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/nature09655","volume":"470","author":"B Bajoghli","year":"2011","unstructured":"Bajoghli B, Guo P, Aghaalei N et al (2011) A thymus candidate in lampreys. Nature 470:90\u201394","journal-title":"Nature"}],"container-title":["Seminars in Immunopathology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s00281-020-00831-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s00281-020-00831-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s00281-020-00831-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T05:44:12Z","timestamp":1697521452000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s00281-020-00831-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,7]]},"references-count":85,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,2]]}},"alternative-id":["831"],"URL":"https:\/\/doi.org\/10.1007\/s00281-020-00831-y","relation":{},"ISSN":["1863-2297","1863-2300"],"issn-type":[{"value":"1863-2297","type":"print"},{"value":"1863-2300","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,7]]},"assertion":[{"value":"27 July 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 December 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 January 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The author does not declare any competing interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}